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An Open Label Phase II Pharmacokinetic and Pharmacodynamic Assessment of the Potential for QTc Prolongation Following First Induction Treatment With CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in Acute Leukemias and MDS Patients

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ClinicalTrials.gov Identifier: NCT02238925
Recruitment Status : Completed
First Posted : September 12, 2014
Results First Posted : November 30, 2017
Last Update Posted : November 30, 2017
Sponsor:
Information provided by (Responsible Party):
Jazz Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE August 14, 2014
First Posted Date  ICMJE September 12, 2014
Results First Submitted Date  ICMJE September 3, 2017
Results First Posted Date  ICMJE November 30, 2017
Last Update Posted Date November 30, 2017
Study Start Date  ICMJE July 2014
Actual Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2017)
Effect of CPX-351 on Cardiac Ventricular Repolarization (QTcF) [ Time Frame: 21 days ]
Time-matched QTcF Changes From Baseline after the start of first infusion
Original Primary Outcome Measures  ICMJE
 (submitted: September 11, 2014)
QT/QTc [ Time Frame: During 1st Induction (up to 5 days) ]
Patients with normal to mild hepatic and renal impairment will be enrolled to assess the effects of CPX-351 on cardiac repolarization following the first induction cycle of CPX-351 as determined by the Fridericia's corrected QT-interval.
Change History Complete list of historical versions of study NCT02238925 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2017)
  • Serum Copper Levels Change From Baseline [ Time Frame: During 1st induction (up to 5 days) ]
    Change from Baseline to Induction 1, Day 5
  • Complete Response Rate [ Time Frame: Following 1st induction, following 2nd induction if applicable ]
  • Tmax [ Time Frame: Induction 1, Day 5 ]
  • Cmax [ Time Frame: Induction 1, Day 5 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 11, 2014)
  • Serum Copper Levels [ Time Frame: Pre-Dose and Up to Day 21 during the 1st Induction, Prior to Every Course of Treatment, Early Termination or End of Study, and 60 Days After the End of Study ]
    Patients with normal to mild and moderately impaired hepatic and renal function will be enrolled in the study to assess copper levels in the serum.
  • Total Drug Plasma PK [ Time Frame: Pre-Dose and Up to Day 21 during the 1st Induction only ]
    Patients with normal to mild and moderately impaired hepatic and renal function will be enrolled in the study to assess total drug levels in the plasma.
  • Total and Encapsulated Drug PK [ Time Frame: Pre-Dose and Up to Day 21 during the 1st Induction only ]
    Patients with normal to mild hepatic and renal impairment will be enrolled in the study to assess total and encapsulated drug levels in the plasma. This will be done in a subset of patients.
  • Efficacy and Safety [ Time Frame: Efficacy and Safety are measured up until the End of Study Period, SAEs are measured up to 30 days from the End of Study Period ]
    All patients enrolled in the study will be assessed for efficacy and safety. Safety will be assessed by monitoring patients for the following: Adverse Events, Serious Adverse Events, Laboratory Safety, Induction Mortality at Day 30 and Day 60, and Clinical Cardiac Safety including ECGs, Cardiac Adverse Events (Grades 1-5, 3-5) and LVEF Changes. Efficacy will be assessed by monitoring patients for a response of CR and CRi in AML, ALL, and MDS. Efficacy and Safety will be assessed while the patients are on the study and for SAEs for 30 days after the End of Study date.
  • Urine Sampling [ Time Frame: Pre-Dose and Up to Day 10 during the 1st Induction only ]
    Patients with moderate renal impairment will be enrolled in the study to assess drug levels in the urine.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Open Label Phase II Pharmacokinetic and Pharmacodynamic Assessment of the Potential for QTc Prolongation Following First Induction Treatment With CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in Acute Leukemias and MDS Patients
Official Title  ICMJE An Open Label Phase II Pharmacokinetic and Pharmacodynamic Assessment of the Potential for QTc Prolongation Following First Induction Treatment With CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in Acute Leukemias and MDS Patients
Brief Summary

The purpose of this study is to assess the effects of CPX-351 on cardiac repolarization, assess plasma drug levels, asses serum copper levels, and assess drug levels in urine.

Efficacy and Safety will be assessed in all patients enrolled to the study.

Detailed Description This study is an open-label, single-arm, Phase II, PK and pharmacodynamic (PD) trial of CPX-351 in patients with documented acute leukemia (AML or ALL) or MDS (IPSS score ≥ 1.5) and suitable for treatment with intensive chemotherapy. Each patient will be screened for hepatic impairment. Hepatic impairment will be assessed using the Child-Pugh system and only patients with a Child-Pugh score <7 points will be eligible for this study. Patients will receive up to two inductions and four consolidation courses. Patients will be monitored for safety (early deaths, adverse events, metabolic changes, etc.) and efficacy (response for AML, ALL, and MDS) while on the study.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia (AML)
  • Acute Lymphoblastic Leukemia (ALL)
  • Myelodysplastic Syndrome (MDS)
Intervention  ICMJE Drug: CPX-351
Study Arms  ICMJE Experimental: CPX-351

Single Arm Study (Patients may receive up to 2 Inductions and 4 Consolidations):

Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion.

Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion.

Consolidations 1-4: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion.

Intervention: Drug: CPX-351
Publications * Lin TL, Newell LF, Stuart RK, Michaelis LC, Rubenstein E, Pentikis HS, Callahan T, Alvarez D, Liboiron BD, Mayer LD, Wang Q, Banerjee K, Louie AC. A phase 2 study to assess the pharmacokinetics and pharmacodynamics of CPX-351 and its effects on cardiac repolarization in patients with acute leukemias. Cancer Chemother Pharmacol. 2019 Jul;84(1):163-173. doi: 10.1007/s00280-019-03856-9. Epub 2019 May 16.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 23, 2016)
26
Original Estimated Enrollment  ICMJE
 (submitted: September 11, 2014)
36
Actual Study Completion Date  ICMJE January 2016
Actual Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Ability to understand and voluntarily sign an informed consent form
  • Age ≥ 18 to ≤ 80 years at the time of signing the informed consent form
  • Life expectancy of at least 3 months
  • Pathological confirmation by bone marrow documenting the following:

    • Newly Diagnosed De novo AML according to WHO criteria except for Acute Promyelocytic Leukemia or patients with known favorable cytogenetics (see exclusion)
    • Newly Diagnosed Secondary AML age <60 years and ≥76 to 80 years, defined as having a history of an antecedent hematologic disorder (myelodysplastic syndromes [MDS], myeloproliferative disease [MPD]or history of cytotoxic treatment for non-hematologic malignancy)
    • Patients with relapsed/refractory AML regardless of cytogenetic risk
    • Patients with relapsed/refractory ALL
    • Patients with MDS (IPSS score ≥ 1.5)
  • Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2
  • Able to adhere to the study visit schedule and other protocol requirements
  • Laboratory values fulfilling the following:

    • Serum Creatinine ≤ 2.0mg/dL
    • Hepatic function with a score of < 7 points according to the Child-Pugh System
    • Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN. Note: If elevated liver enzymes are related to disease; contact medical monitor to discuss.
  • Cardiac ejection fraction ≥50% by ECHO or MUGA
  • Screening and Baseline QTcF (Fridericia's) less than 470 msec
  • Patients with second malignancies in remission may be eligible if there is clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are eligible.
  • All men and women must agree to practice effective contraception during the study period if not otherwise documented to be infertile.

Exclusion Criteria:

  • Patients eligible for participation in Study CLTR0310-301 (Phase III study of CPX-351 NCT01696084) or who have already participated in that study are not eligible for this study.
  • Patients taking medications known to prolong the QTc interval directly or that interact pharmacodynamically with medicines to prolong the QTc interval.
  • Rhythm abnormalities (other than sinus bradycardia with HR < 50 bpm)
  • AV block (other than 1o AV Block with PR > 200 msec)
  • Bundle branch block or QRS ≥ 120 msec
  • Abnormal T wave morphology (other than slight flattening)
  • Pathological U waves
  • Other QRS or T/U morphology preventing accurate determination of QT interval
  • Patients with unexplained syncope, history of or known risk factors for torsade des pointes, including congenital long QT syndrome, or family history of LQTS.
  • Patients with history of and/or current evidence of myocardial impairment (e.g. cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging)
  • Newly diagnosed patients with Acute promyelocytic leukemia [t(15;17)] or favorable cytogenetics, including t(8;21) or inv16
  • Clinical evidence of active CNS leukemic involvement
  • Chemotherapy or other investigational anticancer therapeutic drugs within 1 week prior to study entry unless AEs have resolved and there is no interference with the assessment of efficacy or safety; in the event of rapidly proliferative disease, however, the use of hydroxyurea is permitted up to 12 hours before study entry. Patients with prior bone marrow or stem cell transplant, considered for inclusion, should be discussed with the medical monitor first.
  • Any serious medical condition or psychiatric illness that would prevent the patient from providing informed consent
  • Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent)
  • Active or uncontrolled infection. Patients with any infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for ≥72 hrs. Patients with fevers believed to be due to leukemia or MDS are eligible provided a thorough infection work-up is negative and the patient is clinically and hemodynamically stable.
  • Pregnant or lactating women
  • Hypersensitivity to cytarabine, daunorubicin or liposomal products
  • History of Wilson's disease or other copper-related metabolic disorder
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02238925
Other Study ID Numbers  ICMJE CLTR0310-206
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jazz Pharmaceuticals
Study Sponsor  ICMJE Jazz Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Jazz Pharmaceuticals
Verification Date October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP